Mercury is a highly neurotoxic heavy metal. While the effects of high-level mercury exposure are well-established, the effects of daily low-level exposure on neurocognitive functions and affective states remain controversial. Previous studies have investigated the associations of low-level body mercury with cognitive functions and affective states in adults, but none have examined the associations with brain morphometry using advanced neuroimaging techniques. The deleterious effects of low-level mercury on the developing brain are well-established, particularly from *in utero* exposure, but effects on adults have been inconsistent. This inconsistency may be due to the fully developed blood-brain barrier in adults, which prevents or slows methylmercury accumulation in the central nervous system. Previous studies have also used blood or urinary mercury levels, which are sensitive to short-term exposure variations. Hair mercury levels, however, provide a more reliable indicator of long-term exposure. This study aimed to address these limitations by investigating the associations of hair mercury levels with cognitive functions, depression, and brain structural measures (rGMV, rWMV, FA, and MD) in a large sample of young adults. The researchers hypothesized that hair mercury level would be associated with impaired cognitive functions (particularly processing speed), greater depression, lower rGMV, lower rWMV, lower FA, and higher MD. The neurotoxicity of mercury is a public health concern, particularly given the high fish consumption in countries like Japan, where mercury bioaccumulation in fish is a primary exposure pathway. This study's investigation into the neurocognitive mechanisms in this context is therefore important.

The literature on the effects of low-level mercury exposure on neurocognitive function and mood is mixed. Some studies have shown associations between high blood mercury levels and lower cognitive function, particularly tasks requiring rapid processing. Other studies involving maternal mercury exposure have linked it to poor cognitive performance in offspring. However, other research found no strong evidence for an association between blood mercury levels and neurobehavioral performance in older adults. Surprisingly, a study even reported a negative association between total blood mercury and depression in older adults. In contrast, several studies failed to find an association between dental amalgam or urinary mercury and depression. Basic neuroscience research has consistently demonstrated mercury's neurotoxicity, particularly its damaging effects on myelin and axons, but the mechanisms of neurotoxicity are diverse.

This cross-sectional study included 920 healthy, right-handed young adults (561 males, 359 females; mean age 20.7 years). Hair samples were collected and analyzed for mercury levels using inductively coupled plasma mass spectrometry. Participants underwent neuropsychological testing, including measures of general intelligence, processing speed, working memory, and mood. Magnetic resonance imaging (MRI) was used to acquire high-resolution T1-weighted structural images and diffusion-weighted images. Voxel-based morphometry (VBM) was used to assess rGMV and rWMV, and diffusion tensor imaging (DTI) was used to measure FA and MD. Partial correlation analyses were conducted to examine associations between hair mercury levels and psychological variables, controlling for potential confounding factors. Whole-brain multiple regression analyses were used to investigate the associations between hair mercury levels and brain structural measures, controlling for the same covariates. Multiple comparison corrections were applied using the false discovery rate and threshold-free cluster enhancement (TFCE) methods.

Greater hair mercury levels were significantly associated with: 1. **Lower cognitive performance:** Specifically, lower scores on tasks measuring processing speed (Word-Color task, Color-Word task, Stroop task, and Tanaka B-type intelligence test perception factor). Effect sizes were generally weak (partial correlation coefficients <0.09). 2. **Lower depressive tendency:** Lower scores on the Beck Depression Inventory, indicating a lower susceptibility to depressive states. The effect size was weak (partial correlation coefficient <0.09). 3. **Lower rGMV:** Significantly lower rGMV in the left thalamus and left hippocampus. 4. **Lower rWMV:** Widespread reductions in rWMV across various bilateral white matter areas, including the cerebellar peduncle, pontine crossing tract, corticospinal tract, corpus callosum, and others. 5. **Greater FA:** Higher FA in bilateral white matter areas, partially overlapping with areas showing significant rWMV reductions. 6. **Lower MD:** Lower MD in extensive gray and white matter areas, especially in bilateral frontal lobes and right basal ganglia. Effect sizes for the associations between hair mercury levels and brain structural measures were generally weak (partial correlation coefficients <0.14). Post-hoc analyses examining the associations between significant psychological correlates of hair mercury levels and brain structural changes did not reveal significant results after correction for multiple comparisons.

This study demonstrated weak but significant associations between hair mercury levels and various neurocognitive and brain structural measures in young adults. The findings regarding lower cognitive performance, especially on speed measures, align with previous studies showing mercury's effects on myelination and axonal function. The unexpected negative association between hair mercury and depression could be due to the relatively low-level exposure in this population, in contrast to high-level exposure scenarios associated with depression in past research. The observed increase in FA despite reduced rWMV could be explained by cytoskeletal changes within axons, as suggested by previous animal studies. The negative correlation between MD and hair mercury levels is complex and could involve reduced cerebral blood flow or effects on monoamine systems.

This large-scale study using hair mercury analysis revealed weak but statistically significant associations between chronic low-level mercury exposure and neurocognitive function and brain structure in young adults. Even at typical Japanese exposure levels, mercury levels in hair showed negative correlations with processing speed, and subtle alterations in gray and white matter volumes and diffusion properties. Future longitudinal studies are needed to confirm these findings and establish causality.

This study's cross-sectional design limits the ability to establish causality. The findings may not be generalizable to populations with different educational backgrounds or lifestyles. While the study controlled for many potential confounding factors, residual confounding effects cannot be ruled out completely. Finally, the generally small effect sizes of the observed associations warrant careful interpretation.